Loss of Transcription Factor CREBH Accelerates Diet-Induced Atherosclerosis in Ldlr −/− Mice

Abstract

Objective— Liver-enriched transcription factor cAMP-responsive element-binding protein H (CREBH) regulates plasma triglyceride clearance by inducing lipoprotein lipase cofactors, such as apolipoprotein A-IV (apoA-IV), apoA-V, and apoC-II. CREBH also regulates apoA-I transcription. This study aims to determine whether CREBH has a role in lipoprotein metabolism and development of atherosclerosis. Approach and Results— CREBH-deficient Creb3l3 −/− mice were bred with Ldlr −/− mice creating Ldlr −/− Creb3l3 −/− double knockout mice. Mice were fed on a high-fat and high-sucrose Western diet for 20 weeks. We showed that CREBH deletion in Ldlr −/− mice increased very low–density lipoprotein–associated triglyceride and cholesterol levels, consistent with the impairment of lipoprotein lipase–mediated triglyceride clearance in these mice. In contrast, high-density lipoprotein cholesterol levels were decreased in CREBH-deficient mice, which was associated with decreased production of apoA-I from the liver. The results indicate that CREBH directly activated Apoa1 gene transcription. Accompanied by the worsened atherogenic lipid profile, Ldlr −/− Creb3l3 −/− mice developed significantly more atherosclerotic lesions in the aortas than Ldlr −/− mice. Conclusions— We identified CREBH as an important regulator of lipoprotein metabolism and suggest that increasing hepatic CREBH activity may be a novel strategy for prevention and treatment of atherosclerosis.